PROJECT SUMMARY/ABSTRACT Alzheimer's disease is occurring with increasing prevalence in part due to the increasing number of elders in the US and throughout the world. Despite extensive efforts, the development of therapies for this debilitating disease have been disappointing to date. Interestingly, numerous studies show that the mTOR pathway is elevated in human AD tissue and mouse AD models, and moreover that reducing mTOR activity with rapamycin (at least in the mouse models) reduces AD pathology. An individual's ApoE allele highly influences their risk of AD, and recent mouse models recapitulate these findings. One striking feature of both mTOR and ApoE is that they are both also linked to normal aging. Here, we propose that they may be functionally related and seek to assess in the 5XFAD mouse model whether reduced mTOR signaling is sufficient to rescue AD pathology associated with expression of ApoE4. Another poorly understood feature of AD is that pathology is often more severe in females. This is relevant to mTOR signaling as well, since we have shown sexual dimorphism associated with mTOR signaling and age and further that reducing the activity of downstream substrates has sex-specific benefits. In this proposal, we will test the hypothesis that different mTOR signaling underlies sex-specificity in AD pathology. Together these studies will uncover mechanistic connections between factors clearly implicated in Alzheimer's disease and further shed light on the potential therapeutic benefits of modifying mTOR signaling.